Backlash builds against prasugrel panel decision

Dr. Steven Nissen is the latest high-profile physician to join the pile-on over an FDA advisory panel's decision to exclude an outspoken critic of the antiplatelet drug prasugrel.

Less than two weeks ago the panel voted to recommend approval of the Lilly/Daiichi Sankyo drug, indicated for the treatment of acute coronary syndrome.

Nissen of the Cleveland Clinic, told HeartWire on WebMD's theheart.org, that “in science having a debate and dialogue is what it's all about, and that there is a value in having diversity in this sort of an FDA panel.” Nissen said a single individual is not going to dominate the thinking of a panel and that the exclusion threatens to undermine the credibility of the panel.

Dr. Sanjay Kaul of Cedars-Sinai Medical Center in Los Angeles, an expert in the field of vascular physiology, was asked not to participate in the FDA advisory panel. According to HeartWire, some cardiologists were critical of the decision and questioned why the FDA excluded a member who was likely to bring a critical eye to the panel's proceedings.

Dr. William Boden, of Buffalo General Hospital in New York, who was not part of the panel, told HeartWire that the decision raised some obvious red flags. In addition, an FDA panel member publicly questioned why the Drug Safety and Risk Management subcommittee wasn't involved, while another antiplatelet expert criticized the TRITON-TIMI-38 findings. Other critics have charged that the decision to approve prasugrel appeared predetermined from the start.

According to the FDA, Kaul was not asked to go to the FDA hearing because of an incomplete vetting process that left unanswered questions about possible “intellectual biases.” HeartWire reported that Dr. John Jenkins, the FDA director of the Office of New Drugs, said that on the Friday before the advisory panel hearing, the staff in the cardiovascular and renal division, in the course of their review, became aware of five abstracts presented by Kaul last year at the American Heart Association Scientific Sessions and these analyses, although free from financial conflicts of interest, alerted staff to possible “intellectual bias.”

The abstracts in question included independent analyses of the TRITON-TIMI-38 study, the pivotal prasugrel trial before the advisory panel, and reached numerous conclusions, among them that the clinical benefit associated with prasugrel was less than implied by conventional analyses and that this benefit was driven by nonfatal MI, an end point Kaul concluded was “arguably not the most important of the composite end point."

In addition, Kaul has commented publicly on the TRITON study and suggested that prasugrel fell short in its goal of balancing improved efficacy against the risk of bleeding, according to HeartWire.

Jenkins said that the members of the committee who bring differing perspectives and ask tough questions are welcome, but at the same time, he said that the committee members come to the table with an open mind, so they can give advice based on the data, the presentations and the discussions that are held at the committee meeting.

The FDA stressed that Kaul provided all the necessary information and was forthcoming with the staff when asked questions about the TRITON abstracts. The information about the abstracts, however, was not communicated to the review division in time. Although Jenkins emphasized that Kaul was not excluded, just not fully vetted in time, the decision did not sit well with some cardiologists.

HeartWire reported that Jenkins said he had looked at the abstracts, as well as some of the interviews Kaul has done related to those analyses, and did not see anything that would have precluded him from serving on the committee. Jenkins said that Kaul had raised a lot of tough questions about the end points used in these large cardiovascular studies, and he's done various re-analyses of the data to see how robust the reported findings are. Jenkins said that that's exactly the type of questions that the panel likes to committee members raise.

Jenkins said that the Center for Drug Evaluation and Research, headed-up by Dr. Janet Woodcock, is re-evaluating how to deal with last-minute questions about conflicts for panel members.

Despite the current controversy, leading cardiologists believe that the FDA recommendation to approve prasugrel was the correct one. Nissen told HeartWire that it is known that there are patients that don't respond to clopidogrel and that the individual patient-to-patient variability is very high. Nevertheless, Nissen said that the promise of prasugrel to provide a more consistent antiplatelet effect is valuable.